Tumor metastasis, recurrence, and therapeutic resistance are the main reasons for the failure of clinical cancer treatment. Studies have found that the presence of cancer stem-like cells (CSCs) with stemness characteristics in malignant tumors is a key factor leading to the above undesirable results. However, there are significant limitations to current strategies with traditional molecular drugs for combating CSCs, such as the unsatisfactory in vivo stemness-suppressing efficiency, and the lack of powerful tumor-specific lethal action, resulting in remaining massive bulk tumor cells that can convert to CSCs via epithelial-to-mesenchymal transition (EMT). Although some combination methods using different drugs/therapeutics have been reported to simultaneously combat CSCs and inhibit tumor cells, the complicated procedures and inevitable side effects will pose significant challenges for practical therapeutic applications. Therefore, developing new efficacious strategies that can differentiate CSCs and simultaneously kill tumor cells is expected to achieve efficient tumor treatment and address the issues of tumor recurrence and metastasis.
For solving these challenges, Dr. Yufang Zhu, Dr Chengtie Wu, and Dr Jianlin Shi (Shanghai Institute of Ceramics, Chinese Academy of Sciences) developed a coordination nanomedicine (ZnDHT NM) featuring cascade specific Fe3+ capturing and in situ catalysis mainly by 2,5-dihydroxyterephthalic acid (DHT) complexing Zn2+ in this study.
The results of performance testing and theoretical calculations exhibited that due to the stronger binding force of DHT molecules to Fe3+ compared to other metal ions, ZnDHT NM can specifically capture Fe3+ in the environment, promote the catalytic generation of reactive oxygen species (ROS) by in situ forming a hexacoordinated Fe-DHT conformation with enhanced reducibility, and release Zn2+ from the skeleton. On the one hand, ZnDHT NM can deplete Fe in the tumor microenvironment and promote intracellular ROS production, resulting in synergistically promoting CSC differentiation and inhibiting EMT by separately blocking the Wnt signaling pathway and inducing the FoxO3 activation. On the other hand, ZnDHT NM can release Zn2+, which inactivates glutathione reductase (GR) and downregulates glutathione (GSH) in tumor cells, and combine with the selective ROS production to intervene in the redox homeostasis of tumor cells, activating their apoptosis/ferroptosis pathways.
Further, in the in vivo experiments, the researchers found that this ZnDHT NM, which can simultaneously treat CSCs and tumor cells, effectively inhibited the growth of orthotopic triple-negative breast tumors, and possessed the effect of inhibiting tumor postoperative recurrence and metastasis.
"This study presents an innovative perspective of establishing biosafe nanomedicines to evoke effective therapeutic mechanisms against CSCs and bulk tumor cells concurrently by modulating endogenous substances, which is highly encouraging for cancer nanomedicine design and future tumor therapeutics," Yufang Zhu says.
